Doctor of Philosophy (PhD)
The focus of this dissertation is the development of a novel chlorination reaction utilizing a triphosgene-amine based mixture towards the total synthesis of chlorosulfolipids, a subclass of naturally occurring organohalogen natural products. This novel, mild chlorination reaction will be utilized under a global chlorination strategy to chlorinate multiple alcohol substituents in one synthetic operation. Chapter one details the history of chlorosulfolipids from the early stages of their isolation, relevant structural elucidation techniques, appropriate biosynthetic discoveries, and their biological relevance to a thorough investigation of the total syntheses completed to date. These compounds demonstrate a range of biological activities and have largely gone ignored by synthetic organic chemist for over 40 years since their discovery in freshwater microalga. Chapter two describes our interest in chlorosulfolipids and the importance of developing a synthetic strategy to achieving the total synthesis of these natural products. This chapter introduces our novel chlorination methodology, utilizing a triphosgene-triethylamine mixture to convert unactivated aliphatic primary alcohols to their corresponding primary alkyl chlorides. An unanticipated result arose in which α-branched primary alcohols produced diethylcarbamates and secondary alcohols afforded a mixture of chlorination and diethylcarbamate products. Mechanistic studies revealed a competitive reaction pathway driven by sterics. In chapter three, the optimization for chlorinating secondary alcohols and α-branched primary alcohols is discussed. This chapter focuses on resolving the reactivity concerns posed by the triphosgene-triethylamine activation of primary alcohols. Herein, we discover that a triphosgene-pyridine mixture readily improves the reactivity of secondary alcohols and α-branched primary alcohols to produce their corresponding alkyl chlorides. We also investigate the chlorination of racemic 1,3- and 1,6-diols in our initial attempts at a global chlorination. Chapter four details the stereospecific dichlorination of stereocomplementary 1,3-anti and 1,3-syn diols using a mixture of triphosgene-pyridine. 1,3-anti diols readily reacted to produce the corresponding 1,3-anti dichlorides. It was discovered that 1,3-syn diols must be modified into monosilylethers in order to access the corresponding 1,3-syn dichlorides. We also investigate the chlorination of stereocomplementary 1,3,5-triols to afford the 1,3,5-trichlorides in a global chlorination strategy introducing three C-Cl bonds.
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Villalpando, Andres, "Synthetic Methods Development Towards the Total Synthesis of Chlorosulfolipids" (2015). LSU Doctoral Dissertations. 4003.